4.2 Thrombolysis

The benefit of thrombolytic therapy (“clot busting treatment”) for acute ischaemic stroke  has  been  well  established  [255].  All EU member states have introduced national guidelines for the treatment of acute stroke including thrombolysis, often based on  the guidelines issued by the European Stroke Organisation or the American Stroke  Association.  The  implementation of thrombolysis across Europe since the beginning of this century has transformed acute stroke care, with stroke becoming a treatable condition. One of the main targets of most national stroke strategies is to reduce the time interval from stroke onset to diagnosis in order to increase thrombolysis rates.

Thrombolysis rates have increased in most european and SAFE member countries. Some countries with long-running national stroke audits showed a two- to four-fold increase in thrombolysis rates between 2004  and  2008,  e.g. Germany: 6.0%  to 9.5%,  Sweden:  2.2%  to  7.0%,  and  Poland: 0.9% to 1.2% [163]. UK thrombolysis rates have increased  from  1.8%  in  2008  to  12.2%  in 2014 [237]. Israel reported an increase from 0.4% in 2004 to 5.9% in 2010 in hospitalised stroke patients [71].

Figure 10 shows the proportion of thrombolysed ischaemic stroke patients, as reported in national or large regional audits, or published national estimates. Studies referring to individual hospitals, or stroke unit patients only (e.g. France: 16.7%,[241] were excluded. The time point of data collection is included in the figure and explains some of the variations found.

Figure 10: thrombolysis rates in national/large regional audits or national estimates in the year indicated

References: Bulgaria:[189], Slovakia:[256], Serbia:[230], Malta:[243], Poland:[236], Lithuania:[223], Czech Republic:[257], France:[244], Hungary:[213], Croatia:[258], Spain:[233], Luxembourg:[259], Portugal:[215], Israel:[260], Sweden:[53], Latvia:[230], Norway:[261], UK/Scotland:[262], Ireland:[129], UK (excluding Scotland):[237], Germany:[163, 238], Netherlands:[224], Finland:[9], Austria:[209]

As with stroke unit care, thrombolysis rates vary widely across Europe, but are generally lower in Eastern European countries. Variations between Eastern European countries are also large. The 2015 CEESS Working Group Survey[230] published numbers of thrombolysis procedures undertaken in Eastern European countries   between   2008   and   2014.   In this 7-year period in Romania (22 million population) 205 thrombolysis procedures were undertaken and 149 in Ukraine (45 million),  compared  to  1572  in  Estonia  (1.3 million)  and  3665  in  Slovakia  (5  million). Figure 11 presents these figures converted into average annual thrombolysis rates per 100,000 population for easier comparison.

Both Western (Germany[263, 264], Netherlands[265], Spain[231], Sweden: 7-fold gradient[266])and Eastern European countries have found significant inequalities within their countries between different areas and particularly also between different centres/hospitals.

In Bulgaria, the national rate was below 1%,  but  has  risen  from  0.04%  in  2006  to 0.1%  in  2009,  with  rates  being  higher  in urban centres[189, 267], while in Romania in 2012 thrombolysis was only available in Bucharest, the capital covering around 10%  of  the  population[258].  In  Hungary,  the thrombolysis  rate  was  3.2%  in  2013[213], again with significant differences between national rates and rates in large cities[258, 268]. One Slovakian centre reached thrombolysis rates of 15.8% against a national rate of 0.5- 1%[256]. Polish studies reported thrombolysis rates  of  4.2%  in  rural  areas  compared  to 23.1%  in  urban  areas[269]  and  centre  rates varying between <3% to around 20%[236] In the Czech Republic, the thrombolysis rate was 2.5% nationally in 2009, while a group of centres (SITS registered) achieved 4.3% in 2007[270].

Figure 11: Average annual thrombolysis rate per 100,000 population, 2008-2014[230]

Again, comparisons between studies have limitations as different studies reporting thrombolysis rates often investigate different subgroups. Denominator populations vary between all stroke patients, all ischaemic stroke patients, hospitalised stroke patients (e.g. national audits), stroke unit patients (e.g. Austrian Stroke Unit Register), or refer to a specific region (population-based registers) or individual stroke centres only (31% in one Finnish centre in Helsinki[210], 22% in 2012 in large Dutch University hospital[271], 11% in University hospital Verona, Italy[193], 0% in two Lithuanian centres in 2006/7[272].

The 2006 Helsingborg Declaration states as a goal for 2015 that all countries aim to establish a system for the routine collection of data needed to evaluate the quality of stroke management, including patient safety issues. However, national audits are only undertaken in a small number of countries (chapter 1.1.). Standardised, internationally agreed datasets would allow accurate international benchmarking. The Safe Implementation of Thrombolysis in Stroke (SITS) Registry, started in 1996, contains standardised data on thrombolysis procedures performed in each country, but shows significant variations between countries in terms of the percentage of centres providing data (Appendix 1, Table 3). Due to these highly variable recruitment rates SITS data is currently a poor measure of national thrombolysis rates and country-level comparisons.

The international Registry of Stroke Care Quality (RES-Q) was launched in May 2016 by ESO, targeting mainly Eastern European countries, but aiming to collate internationally agreed care quality measures.

So, due to the variations between studies, only rough indications and  trends  can  be observed when comparing between countries.   Data   is   more   reliable   when looking  at   trends   over   time within   a smaller  subgroup  (single centre,  region, hospitalised   patients   only).     Observing trends over time is a valuable part of stroke observational studies, as they provide proof that   organisational   change   is   efficient. Additionally, monitoring performance itself helps to improve care quality[163].

Structural changes to stroke services were found to be associated with higher thrombolysis rates in European studies and supported by a recent review[274]:

〉 hospital pre-notification (Portugal[216]) and reduction of door-to-needle time (Netherlands[224])

〉 implementation of stroke unit care (Germany[275], Sweden[266]: thrombolysis 5-times more likely in stroke unit)

〉centralization of stroke services (Denmark[250], UK[244]: rise in thrombolysis rate from 3 to 12%)

A further factor that has contributed to increased thrombolysis rates was the approval of the extended time window for thrombolysis from 3 to 4.5 hours by the European Medicines Agency in November 2010. A rapid implementation into clinical practice was observed leading to an increase in thrombolysis rates from 8.6% before to 11.7% in a large hospital-based study in Germany[276]. Additionally, changes in reimbursement systems are also relevant.

In Poland, thrombolysis was initiated within the Polish National Cardiovascular Disease Prevention and Treatment Program POLKARD and was subject to reimbursement limits. Since 2009 thrombolysis is reimbursed through the National Health Fund with no reimbursement limits. Thrombolysis rates increased from 4.3% to 7.6% in a hospital based observational study[277].

“Treatment with rt-PA in ischemic stroke was introduced … within the frame of the Polish Ministry of Health National Cardiovascular Disease Prevention and Treatment Program POLKARD. As the funds in POLKARD were limited, the number of centres and total number of patients treated with thrombolysis in each centre were limited. This resulted in an unusual situation, where legally registered treatment could not be administered to all eligible and insured patients. Beginning with 2009, thrombolytic treatment in acute stroke has been reimbursed by NFZ (National Health Fund, Narodowy Fundusz Zdrowia)… When reimbursement limits were eliminated, higher proportion of patients with acute ischemic stroke could be treated with intravenous thrombolysis …”[277].

Despite improvements over the last decade, thrombolysis rates are still significantly below expectations in Europe.

This is particularly true for Eastern Europe, but also for Western European countries. In Germany, only 60% of eligible patients were found to have received thrombolysis in 2012[238], and 42% in Italy and Portugal[216, 278]. Under-performance was also reported from France[212] and the Netherlands (5-7% actual rate compared to 25% potential rate[187], whereas the National Stroke Audit for England, Wales and Northern Ireland concluded that 81% of eligible patients were thrombolysed in 2014[237].

Barriers to the delivery of thrombolysis are numerous and complex[279].

The most significant barriers include pre- and in-hospital delays.   Within pre-hospital delays, poor public knowledge  as  well  as inadequately trained ambulance staff has been identified as significant factor in European studies (review[180], Poland[269], Sweden, Denmark, and Norway[280], Norway[281, 282], England[283], Netherlands[187, 284,  285]).  In-hospital  delays  were  related  to insufficient  in-hospital  routines,  i.e.  the existence of and adherence to specific protocols[280, 286], a lack of  specialised units or staff[275, 287, 288], lack of diagnostic equipment[228], a  de-centralised  system of stroke care[284] and low thrombolysis numbers[223,   289].    Additionally,    financial considerations  are  important.  In  35%  of Czech centres thrombolysis was found to be restricted due to financial limitations[270], and, as above, re-imbursement schemes limited thrombolysis in Poland until 2008[277].

Accordingly, improvements to the factors listed above have been suggested or found to improve thrombolysis rates further.

Thrombectomy (mechanically removing blood clots) is currently being introduced in many European countries by including it in national stroke guidelines and implementing the necessary health care facilities in specialised centres. While there are several countries where it is not yet available at all (Bulgaria, Iceland, Macedonia[9, 178]), in most countries it is not available 24/7 or in all regions. Future effort will be required to implement a network of collaborating hospitals with regional referral centres that makes thrombectomy more widely available to patients.

In summary, thrombolysis rates have increased significantly over the last decade. However, large variations exist between and  within  countries.  Even  countries  with comparatively high thrombolysis rates have  room  for  improvement.  Apart  from improving public stroke knowledge, several organisational factors have been found to improve rates and merit further assessment of their effectiveness and feasibility according to the individual country’s context.

Accurate international comparisons of stroke care quality, e.g. thrombolysis rates, are difficult, because of a lack of standardised, internationally agreed and widely collected  quality measures. Within the EU, there are numerous stroke registers on a local, regional, national, and sometimes international level collecting varied data with different methods. International stroke registers with standardised datasets exist, e.g. SITS-MOST and RES-Q (see example), but data reporting is voluntary and therefore coverage varies significantly.

If used more extensively these registers could contribute to reliable international benchmarking, providing valuable insights into inequalities of care and the performance of different healthcare systems and helping to focus on areas where improvement is most needed.